Bortezomib is a modified dipeptidyl boronic acid derivative derived from leucine and phenyl alanine. The chemical name is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid and represented as follows:

Bortezomib is marketed as Velcade and Bortenat (generic), and is used to treat lymphomas.
The patent U.S. Pat. No. 5,780,454 discloses bortezomib, while WO2005097809 describes large scale preparation of bortezomib. There are other patent applications such as WO2009004350, WO2009036281, WO2010146172, WO2011087822, WO2011098963, WO2012048745 and IN patent application no. 2638/MUM/2012 which describe various processes for synthesis of bortezomib.
Boronic acid and its ester compounds display a variety of pharmaceutically useful biological activities. The patent U.S. Pat. No. 4,499,082 (1985) discloses peptide boronic acids as inhibitors of certain proteolytic enzymes. The patents U.S. Pat. No. 5,187,157 (1993), U.S. Pat. No. 5,242,904 (1993) and U.S. Pat. No. 5,250,720 (1993) describe a class of peptide boronic acids that inhibit trypsin-like proteases. The patents U.S. Pat. No. 5,169,841 (1992) discloses N-terminally modified peptide boronic acids that inhibit the action of rennin and U.S. Pat. No. 5,106,948 (1992), discloses certain tripeptide boronic acid compounds that inhibit the growth of cancer cells. The patents U.S. Pat. No. 5,780,454 (1998), U.S. Pat. No. 6,066,730 (2000), U.S. Pat. No. 6,083,903 (2000), and U.S. Pat. No. 6,297,217 (2001) relate to peptide boronic ester and acid compounds useful as proteasome inhibitors.
In the patent application WO9835691, it is described that proteasome inhibitors including boronic acid compounds are useful for treating infarcts such as those that occur during stroke or myocardial infarction. WO9915183 describes that proteasome inhibitors are useful for treating inflammatory and autoimmune diseases. Moreover, alkylboronic acids are relatively difficult to obtain in analytically pure form. Snyder et al., J: Am. Chew. Soc., 3611 (1958), teaches that alkylboronic acid compounds readily form boroxines (anhydrides) under dehydrating conditions and their boroxines are often air-sensitive. Korcek et al., J. Chem. Soc., Perkin Trans. 2 242 (1972), teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid. These difficulties were limiting the pharmaceutical utility of boronic acid compounds.
Bortezomib (a boronic acid compound), in its solid state as a pure API existed in the form of highly water insoluble boroxine, a cyclic boronic acid anhydride. When placed in water, the boroxine dissociated to form equilibrium between itself and the monomeric bortezomib resulting in an apparent water solubility of about 0.5-1 mg/ml which was not sufficient for formulation purposes. In order to deal with such issues, the innovator company in their patent WO2002059130 application has described a stable formulation containing mannitol ester of bortezomib. The application '9130 also relates to a process of preparing such formulation by first dissolving the bortezomib in warm (temperature around 45±2° C.) TBA (tertiary butyl alcohol), then adding water and mannitol (1% bulking agent), followed by freeze drying. On reconstitution, Bortezomib was found to rapidly dissolve and more soluble in water due to the in situ formation of boronic acid esters by reaction with diol groups of mannitol during the alcohol lyophilisation or freeze-drying process. So, the FDA approved drug Bortezomib is now available as a mannitol boronic ester which in its reconstituted form consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride from as a trimeric boroxine, as described below in FIG. 1.

However, this process of making Bortezomib mannitol ester as mentioned in the prior art has certain limitations like, a) involves a step of freeze-drying or alcohol lyophilisation which requires the use of very expensive refrigeration-drying machine or freeze-dryer or alcohol lyophiliser, that makes the process an economical liability on pharmaceutical companies while manufacturing Bortezomib mannitol ester on an industrial scale; b) involves use of large quantities of TBA (tertiary butyl alcohol) as one of the solvents, that results into formation of unstable butylboronic acid which is readily oxidized in air; c) a much complicated process; and d) involves a process that uses larger volumes of water and is carried out at a higher temperature, which may result in formation of a larger amount of degradation impurity (X), as depicted in the reaction below,
There is thus a need in the art for an improved process for preparing Bortezomib mannitol esters. Ideally, such improved processes should be convenient, industrially feasible, and economical which at the same time should provide good yield, chemical stability, pure product substantially free of impurities and easily accessible treatment to a subject in need of boronic acid therapy.